Treatment Of Prion Diseases Research Articles

Chapter 21 - Symptomatic treatment, care, and support of CJD patients

Prion diseases (e.g., Creutzfeldt-Jakob disease) are rapidly progressive neurodegenerative diseases that are invariably fatal. Diagnosing prion disease can be difficult and can lead to frustration. There is no currently available disease-altering treatment for prion diseases and the care and management of affected patients are directed towards symptomatic relief and quality of life. In this chapter, we highlight the many unique challenges of prion disease and how they affect care and management strategies. Symptomatic treatment follows many of the same principles observed in geriatric and/or hospice care, with some important differences due to disease-specific characteristics. We provide an overview of pharmacologic and nonpharmacologic strategies for managing symptoms of prion disease. Education and psychosocial support are also very important in managing patients and families affected by the illness and are discussed in detail. Readers of this chapter will understand the context of caring for a patient with prion disease and will be supplied with practical tools for managing symptoms and educating other healthcare personnel and caregivers. Additional resources for assistance in the care of prion disease patients are also discussed.

Chapter 24 - Clinical trials

Arguably the most important goal of prion research is the discovery of a safe and effective treatment for the human diseases. The final stages of the pathway to develop a treatment require clinical trials. Choices about how a trial is designed and conducted have a large impact on the chances of success. The gold-standard large randomized double-blind placebo-controlled study, which minimizes sources of bias and has been incredibly successful in other diseases, has been hard to achieve in Creutzfeldt-Jakob disease principally because of the rarity and rapidity of the clinical syndrome. To date, clinical trials have been restricted to repurposed compounds, doxycycline, quinacrine, pentosan polysulfate (PPS), and flupertine. In most cases, these trials have used survival as an endpoint, which, whilst clearcut, has limitations. Biomarkers have played a strong role in diagnosis and entry criteria, but only a limited role as secondary outcome measures. Recent developments suggest some possible improvements in trial design by use of new outcome measures that have more favorable properties, and biomarkers of neuronal damage and/or prion seeding activity. Alternative patient populations, including those at risk of genetic forms of prion disease, warrant more consideration. In the future, improved trial designs will be employed to test compounds designed specifically to treat prion diseases.

DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction and neuronal death.

SummaryMitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin‐like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP106–126 in vitro as well as in prion strain‐infected hamster brain in vivo. Suppression of DLP1 expression by DPL1 RNAi inhibited prion‐induced mitochondrial fragmentation and dysfunction (measured by ADP/ATP ratio, mitochondrial membrane potential, and mitochondrial integrity). We also demonstrated that DLP1 RNAi is neuroprotective against prion peptide in N2a cells as shown by improved cell viability and decreased apoptosis markers, caspase 3 induced by PrP106–126. On the contrary, overexpression of DLP1 exacerbated mitochondrial dysfunction and cell death. Moreover, inhibition of DLP1 expression ameliorated PrP106–126‐induced neurite loss and synaptic abnormalities (i.e., loss of dendritic spine and PSD‐95, a postsynaptic scaffolding protein as a marker of synaptic plasticity) in primary neurons, suggesting that altered DLP1 expression and mitochondrial fragmentation are upstream events that mediate PrP106–126‐induced neuron loss and degeneration. Our findings suggest that DLP1‐dependent mitochondrial fragmentation and redistribution plays a pivotal role in PrPS c‐associated mitochondria dysfunction and neuron apoptosis. Inhibition of DLP1 may be a novel and effective strategy in the prevention and treatment of prion diseases.

The function of the cellular prion protein in health and disease.

The essential role of the cellular prion protein (PrPC) in prion disorders such as Creutzfeldt-Jakob disease is well documented. Moreover, evidence is accumulating that PrPC may act as a receptor for protein aggregates and transduce neurotoxic signals in more common neurodegenerative disorders, such as Alzheimer's disease. Although the pathological roles of PrPC have been thoroughly characterized, a general consensus on its physiological function within the brain has not yet been established. Knockout studies in various organisms, ranging from zebrafish to mice, have implicated PrPC in a diverse range of nervous system-related activities that include a key role in the maintenance of peripheral nerve myelination as well as a general ability to protect against neurotoxic stimuli. Thus, the function of PrPC may be multifaceted, with different cell types taking advantage of unique aspects of its biology. Deciphering the cellular function(s) of PrPC and the consequences of its absence is not simply an academic curiosity, since lowering PrPC levels in the brain is predicted to be a powerful therapeutic strategy for the treatment of prion disease. In this review, we outline the various approaches that have been employed in an effort to uncover the physiological and pathological functions of PrPC. While these studies have revealed important clues about the biology of the prion protein, the precise reason for PrPC's existence remains enigmatic.

Therapeutic effect of autologous compact bone-derived mesenchymal stem cell transplantation on prion disease.

Prion diseases are fatal neurodegenerative disorders of humans and animals and no effective treatments are currently available. Allogenic transplantation of immortalized human mesenchymal stem cells (MSCs) can prolong the survival of mice infected with prions. However, autologous transplantation is an appropriate model for evaluating the effects of MSCs on prion diseases. Therefore, we isolated and purified MSCs from the femur and tibia of mice as compact bone-derived MSCs (CB-MSCs). Flow cytometric analysis showed that CB-MSCs were negative for myeloid stem cell-derived cell markers CD11b and CD45, but positive for molecules such as Sca-1, CD105 and CD90.2, which are reported to be expressed on MSCs. The ability of CB-MSCs to migrate to brain extracts from prion-infected mice was confirmed by an in vitro migration assay. Intra-hippocampus transplantation of CB-MSCs at 120 days post-inoculation marginally but significantly prolonged the survival of mice infected with the Chandler prion strain. The transplantation of CB-MSCs did not influence the accumulation of disease-specific prion protein. However, the CB-MSC transplantation enhanced microglial activation, which appeared to be polarized to the M2-type activation state. These results suggest that autologous MSC transplantation is a possible treatment for prion diseases, while the modification of microglial activation may be a therapeutic target for neurodegenerative diseases.

Prion disease and endoplasmic reticulum stress pathway correlations and treatment pursuits

AbstractBackground: Transmissible spongiform encephalopathies are a collection of rare neurodegenerative disorders characterized by loss of neuronal cells, astrocytosis, and plaque formation. The causative agent of these diseases is thought to be abnormally folded prions and is characterized by a conformational change from normal, cellular prion protein (PrPc) to the abnormal form (PrPTSE). Although, there is evidence that normal prion protein can contribute to these disorders. The unfolded protein response, a conserved series of pathways involved in resolving stress associated with unfolded protein accumulation in the Endoplasmic Reticulum (ER), has been shown to play a role in regulating the development of prion diseases. Methods: This review chose papers based on their relevance to current studies involved in prion protein synthesis and transformation, identifies various links between prion diseases and ER stress, and reports on current and potential treatments as they relate to ER stress and prion diseases. Conclusion: For the advancement of prion disease treatment, it is important to understand the mechanisms involved in prion formation, and ER stress is implicated in prion disease progression. Therefore, targeting the ER or pathways involved in response to stress in the ER may help us treat prion diseases.

Dual MicroRNA to Cellular Prion Protein Inhibits Propagation of Pathogenic Prion Protein in Cultured Cells.

Prion diseases are fatal transmissible neurodegenerative disorders affecting humans and various mammals. In spite of intensive efforts, there is no effective cure or treatment for prion diseases. Cellular forms of prion protein (PrPC) is essential for propagation of abnormal isoforms of prion protein (PrPSc) and pathogenesis. The effect of an artificial dual microRNA (DmiR) on PrPC suppression and resultant inhibition of prion replication was determined using prion-infectible cell cultures: differentiated C2C12 culture and primary mixed neuronal and glial cells culture (MNGC). Processing of DmiR by prion-susceptible myotubes, but not by reserve cells, in differentiated C2C12 culture slowed prion replication, implying an importance of cell type-specific PrPC targeting. In MNGC, reduction of PrPC with DmiR was effective for suppressing prion replication. MNGC lentivirally transduced with non-targeting control miRNAs (scrambled) reduced prion replication at a level similar to that with a synthetic analogue of viral RNA, poly I:C. The results suggest that a synergistic combination of the immunostimulatory RNA duplexes (miRNA) and PrPC silencing with DmiR might augment a therapeutic potential of RNA interference.

Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells.

Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear.IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Aβ oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region.

Truncated prion protein PrP226* - A structural view on its role in amyloid disease

In the brain of patients with transmissible spongiform encephalopathies, besides PrPSc aggregates, deposition of truncated PrP molecules was described. Jansen et al. reported two clinical cases with deposition of C-terminally truncated PrP, one of them ending with Tyr226. We have previously described the discovery of monoclonal antibody V5B2 that selectively recognizes this version of the prion protein, which we called PrP226*. Using monoclonal antibody V5B2 we showed that accumulation of PrP226* is characteristic for most types of human and animal TSEs. Its distribution correlates to the distribution of PrPSc aggregates. To gain insight into the structural basis of its presence and distribution in PrP aggregates, we have determined the NMR structure of recombinant PrP226*. The structure of the protein consists of a disordered N-terminal part (residues 90–125) and a structured C-terminal part (residues 126–226). The C-terminal segment consists of four α-helices and a short antiparallel β-sheet. Our model predicts a break in the C-terminal helix and reorganized hydrophobic interactions between helix α3 and β2−α2 loop due to the shorter C-terminus. The structural model gives information on the possible role of the protein in the development of amyloid disease and can serve as a foundation to develop tools for prevention and treatment of prion diseases.

Quiescin-sulfhydryl oxidase inhibits prion formation in vitro.

Prions are infectious proteins that cause a group of fatal transmissible diseases in animals and humans. The scrapie isoform (PrPSc) of the cellular prion protein (PrPC) is the only known component of the prion. Several lines of evidence have suggested that the formation and molecular features of PrPSc are associated with an abnormal unfolding/refolding process. Quiescin-sulfhydryl oxidase (QSOX) plays a role in protein folding by introducing disulfides into unfolded reduced proteins. Here we report that QSOX inhibits human prion propagation in protein misfolding cyclic amplification reactions and murine prion propagation in scrapie-infected neuroblastoma cells. Moreover, QSOX preferentially binds PrPSc from prion-infected human or animal brains, but not PrPC from uninfected brains. Surface plasmon resonance of the recombinant mouse PrP (moPrP) demonstrates that the affinity of QSOX for monomer is significantly lower than that for octamer (312 nM vs 1.7 nM). QSOX exhibits much lower affinity for N-terminally truncated moPrP (PrP89-230) than for the full-length moPrP (PrP23-231) (312 nM vs 2 nM), suggesting that the N-terminal region of PrP is critical for the interaction of PrP with QSOX. Our study indicates that QSOX may play a role in prion formation, which may open new therapeutic avenues for treating prion diseases.

Distinct effects of mutations on biophysical properties of human prion protein monomers and oligomers.

Prion diseases are a group of fatal neurodegenerative illnesses, resulting from the conformational conversion of the cellular prion protein (PrPC) into a misfolded form (PrPSc). The formation of neurotoxic soluble prion protein oligomer (PrPO) is regarded as a key step in the development of prion diseases. About 10%-15% of human prion diseases are caused by mutations in the prion protein gene; however, the underlying molecular mechanisms remain unclear. In the present work, we compared the biophysical properties of wild-type (WT) human prion protein 91-231 (WT HuPrP91-231) and its disease-associated variants (P105L, D178N, V203I, and Q212P) using several biophysical techniques. In comparison with WT HuPrPC, the Q212P and D178N variants possessed greatly increased conversion propensities of PrPC into PrPO, while the V203I variant had dramatically decreased conversion propensity. The P105L variant displayed a similar conversion propensity to WT HuPrPC Guanidine hydrochloride-induced unfolding experiments ranked the thermodynamic stabilities of these proteins as Q212P<D178N<WT ≈ P105L<V203I. It was thus suggested that the conversion propensities of the prion proteins are closely associated with their thermodynamic stabilities. Furthermore, structural comparison illustrated that Q212P, D178N, and V203I variants underwent larger structural changes compared with WT HuPrPC, while the P105L variant adopted a similar structure to the WT HuPrPC The mutation-induced structural perturbations might change the thermodynamic stabilities of the HuPrPC variants, and correspondingly alter the conversion propensities for these prion proteins. Our results extend the mechanistic understanding of prion pathogenesis, and lay the basis for the prevention and treatment of prion diseases.

Parkin Overexpression Ameliorates PrP106-126-Induced Neurotoxicity via Enhanced Autophagy in N2a Cells.

Transmissible spongiform encephalopathies (TSEs) are caused by the accumulation of the abnormal prion protein scrapie (PrPSc). Prion protein aggregation, misfolding, and cytotoxicity in the brain are the major causes of neuronal dysfunction and ultimate neurodegeneration in all TSEs. Parkin, an E3 ubiquitin ligase, has been studied extensively in all major protein misfolding aggregating diseases, especially Parkinson's disease and Alzheimer's disease, but the role of parkin in TSEs remains unknown. Here we investigated the role of parkin in a prion disease cell model in which neuroblastoma2a (N2a) cells were treated with prion peptide PrP106-126. We observed a gradual decrease in the soluble parkin level upon treatment with PrP106-126 in a time-dependent manner. Furthermore, endogenous parkin colocalized with FITC-tagged prion fragment106-126. Overexpression of parkin in N2a cells via transfection repressed apoptosis by enhancing autophagy. Parkin-overexpressing cells also showed reductions in apoptotic BAX translocation to the mitochondria and cytochrome c release to the cytosol, which ultimately inhibited activation of proapoptotic caspases. Taken together, our findings reveal a parkin-mediated cytoprotective mechanism against PrP106-126 toxicity, which is a novel potential therapeutic target for treating prion diseases.

Prion infection impairs lysosomal degradation capacity by interfering with rab7 membrane attachment in neuronal cells.

Prions are proteinaceous infectious particles which cause fatal neurodegenerative disorders in humans and animals. They consist of a mostly β-sheeted aggregated isoform (PrPSc) of the cellular prion protein (PrPc). Prions replicate autocatalytically in neurons and other cell types by inducing conformational conversion of PrPc into PrPSc. Within neurons, PrPSc accumulates at the plasma membrane and in vesicles of the endocytic pathway. To better understand the mechanisms underlying neuronal dysfunction and death it is critical to know the impact of PrPSc accumulation on cellular pathways. We have investigated the effects of prion infection on endo-lysosomal transport. Our study demonstrates that prion infection interferes with rab7 membrane association. Consequently, lysosomal maturation and degradation are impaired. Our findings indicate a mechanism induced by prion infection that supports stable prion replication. We suggest modulation of endo-lysosomal vesicle trafficking and enhancement of lysosomal maturation as novel targets for the treatment of prion diseases.

Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein.

Prion diseases are fatal neurodegenerative disorders for which there is no effective treatment. Because the cellular prion protein (PrP(C)) is required for propagation of the infectious scrapie form of the protein, one therapeutic strategy is to reduce PrP(C) expression. Recently FK506, an inhibitor of the FKBP family of peptidyl prolyl isomerases, was shown to increase survival in animal models of prion disease, with proposed mechanisms including calcineurin inhibition, induction of autophagy, and reduced PrP(C) expression. We show that FK506 treatment results in a profound reduction in PrP(C) expression due to a defect in the translocation of PrP(C) into the endoplasmic reticulum with subsequent degradation by the proteasome. These phenotypes could be bypassed by replacing the PrP(C) signal sequence with that of prolactin or osteopontin. In mouse cells, depletion of ER luminal FKBP10 was almost as potent as FK506 in attenuating expression of PrP(C). However, this occurred at a later stage, after translocation of PrP(C) into the ER. Both FK506 treatment and FKBP10 depletion were effective in reducing PrP(Sc) propagation in cell models. These findings show the involvement of FKBP proteins at different stages of PrP(C) biogenesis and identify FKBP10 as a potential therapeutic target for the treatment of prion diseases.

Treatment of Prion Disease with Heterologous Prion Proteins

Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep are fatal neurodegenerative diseases for which there is no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrPC) into a protease resistant infectious form (PrPsc or PrPres). Both in vitro (cell culture and cell free conversion assays) and in vivo (animal) studies have demonstrated the strong dependence of this conversion process on protein sequence homology between the initial prion inoculum and the host’s own cellular prion protein. The presence of non-homologous (heterologous) proteins is often inhibitory to this conversion process. We hypothesize that the presence of heterologous prion proteins from one species might therefore constitute an effective treatment for prion disease in another species. To test this hypothesis, we infected mice intracerebrally with murine adapted RML-Chandler scrapie and treated them with heterologous prion protein (purified bacterially expressed recombinant hamster prion protein) or vehicle alone. Treated animals demonstrated reduced disease associated pathology, decreased accumulation of protease-resistant disease-associated prion protein, with delayed onset of clinical symptoms and motor deficits. This was concomitant with significantly increased survival times relative to mock-treated animals. These results provide proof of principle that recombinant hamster prion proteins can effectively and safely inhibit prion disease in mice, and suggest that hamster or other non-human prion proteins may be a viable treatment for prion diseases in humans.

Current Trends in the Treatment of Prion Disease

Prion disease refers to a group of neurodegenerative disorders characterized by a relentlessly progressing clinical course leading to death. The pathogenesis of prion disease is the conversion of a normal type prion protein (PrP(C)) into a pathological isoform with protease resistance (PrP(Sc)), which accumulates in the brain. A number of therapeutic agents, including quinacrine, doxycycline, and pentosan polysulphate have shown preventive effects against the conversion of PrP(C) into PrP(Sc) in experimental studies; however, none of these agents have shown satisfactory efficacy in clinical trials. As the clinical course of prion disease varies, the design of clinical trials has been particularly difficult. These limitations must be overcome, and it is necessary to determine a basis for clinical trials with the new candidate agents.

Clinical update of Jakob-Creutzfeldt disease.

The present review discusses recent clinical data on diagnosis, new forms, and treatment of human prion diseases, and briefly summarizes research suggesting prion-like mechanisms in other neurodegenerative diseases. When proper sequences are performed, MRI has high diagnostic utility in prion disease, but there are issues with interpretation of images. The spectrum of MRI's utility for diagnosis and understanding human prion disease is still being explored. Two recent diffusion tensor imaging studies quantified changes in the gray and white matter in sporadic Jakob-Creutzfeldt disease, with unexpected results. The diagnostic utility of cerebrospinal fluid biomarkers has been controversial. A few studies showed that amplification methods can detect prions in either cerebrospinal fluid, olfactory epithelium, blood and/or urine in various human prion diseases. Additional cases of variably protease-sensitive prionopathy have led to a broader understanding of this novel sporadic prion disease. A few new mutations causing genetic prion disease, one with a very atypical presentation, have been identified. Although recent human prion disease treatment trials did not show benefit, they have improved our understanding, and led to better quantification, of the progression of these disorders. Lastly, we briefly summarize the increasing evidence that many nonprion neurodegenerative proteinopathies might spread in the brain by a prion-like mechanism. New prion detection methods appear promising, but need to be replicated with larger sample sizes. Identification of novel forms of human prion disease might better elucidate the full spectrum of prion diseases and expand our understanding of their pathogenesis.

Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease.

Prion diseases are fatal neurodegenerative disorders associated with the conversion of cellular prion protein (PrPC) into its aberrant infectious form (PrPSc). There is no treatment available for these diseases. The bile acids tauroursodeoxycholic acid(TUDCA) and ursodeoxycholic acid (UDCA) have been recently shown to be neuroprotective in other protein misfolding disease models, including Parkinson’s, Huntington’s and Alzheimer’s diseases, and also in humans with amyotrophic lateral sclerosis.Here, we studied the therapeutic efficacy of these compounds in prion disease. We demonstrated that TUDCA and UDCA substantially reduced PrP conversion in cell-free aggregation assays, as well as in chronically and acutely infected cell cultures. This effect was mediated through reduction of PrPSc seeding ability, rather than an effect on PrPC. We also demonstrated the ability of TUDCA and UDCA to reduce neuronal loss in prion-infected cerebellar slice cultures. UDCA treatment reduced astrocytosis and prolonged survival in RML prion-infected mice. Interestingly, these effects were limited to the males, implying a gender-specific difference in drug metabolism. Beyond effects on PrPSc, we found that levels of phosphorylated eIF2 were increased at early time points, with correlated reductions in postsynaptic density protein 95. As demonstrated for other neurodegenerative diseases, we now show that TUDCA and UDCA may have a therapeutic role in prion diseases, with effects on both prion conversion and neuroprotection. Our findings, together with the fact that these natural compounds are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans, make these compounds promising alternatives for the treatment of prion diseases. Prion diseases are fatal neurodegenerative diseases that are transmissible to humans and other mammals. There are no disease-modifying therapies available, despite decades of research. Treatment targets have included inhibition of protein accumulation,clearance of toxic aggregates, and prevention of downstream neurodegeneration. No one target may be sufficient; rather, compounds which have a multimodal mechanism, acting on different targets, would be ideal. TUDCA and UDCA are bile acids that may fulfill this dual role. Previous studies have demonstrated their neuroprotective effects in several neurodegenerative disease models, and we now demonstrate that this effect occurs in prion disease, with an added mechanistic target of upstream prion seeding. Importantly, these are natural compounds which are orally bioavailable, permeable to the blood-brain barrier, and U.S.Food and Drug Administration-approved for use in humans with primary biliary cirrhosis. They have recently been proven efficacious in human amyotrophic lateral sclerosis. Therefore, these compounds are promising options for the treatment of prion diseases.

Targeting the endoplasmic reticulum in prion disease treatment: breakthroughs and challenges

Targeting the endoplasmic reticulum in prion disease treatment: breakthroughs and challenges

Inhibitory effects of NAMI-A-like ruthenium complexes on prion neuropeptide fibril formation.

Prion diseases are a group of infectious and fatal neurodegenerative disorders caused by the conformational conversion of a cellular prion protein (PrP) into its abnormal isoform PrP(Sc). PrP106-126 resembles PrP(Sc) in terms of physicochemical and biological characteristics and is used as a common model for the treatment of prion diseases. Inhibitory effects on fibril formation and neurotoxicity of the prion neuropeptide PrP106-126 have been investigated using metal complexes as potential inhibitors. Nevertheless, the binding mechanism between metal complexes and the peptide remains unclear. The present study is focused on the interaction of PrP106-126 with NAMI-A and NAMI-A-like ruthenium complexes, including KP418, KP1019, and KP1019-2. Results demonstrated that these ruthenium complexes could bind to PrP106-126 in a distinctive binding mode through electrostatic and hydrophobic interactions. NAMI-A-like ruthenium complexes can also effectively inhibit the aggregation and fibril formation of PrP106-126. The complex KP1019 demonstrated the optimal inhibitory ability upon peptide aggregation, and cytotoxicity because of its large aromatic ligand contribution. The studied complexes could also regulate the copper redox chemistry of PrP106-126 and effectually inhibit the formation of reactive oxygen species. Given these findings, ruthenium complexes with relatively low cellular toxicity may be used to develop potential pharmaceutical products against prion diseases.